Conditional knockout of pyruvate dehydrogenase in mouse pancreatic β‑cells causes morphological and functional changes

Wang,Xiao; Lai,Shuchang; Ye,Yanshi; Hu,Yuanyuan; Pan,Daoyan; Bai,Xiaochun; Shen,Jie

doi:10.3892/mmr.2020.10993

Conditional knockout of pyruvate dehydrogenase in mouse pancreatic β‑cells causes morphological and functional changes

Authors:
- Xiao Wang
- Shuchang Lai
- Yanshi Ye
- Yuanyuan Hu
- Daoyan Pan
- Xiaochun Bai
- Jie Shen
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Affiliations: Shunde Hospital of Southern Medical University, Foshan, Guangdong 528308, P.R. China, The Second Affiliated Hospital of Hainan Medical University, Haikou, Hainan 570100, P.R. China, Department of Endocrinology, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510000, P.R. China, Shenzhen Nan Shan Hospital, Shenzhen, Guangdong 518052, P.R. China
Published online on: February 20, 2020 https://doi.org/10.3892/mmr.2020.10993
Pages: 1717-1726
Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Diabetes mellitus is a metabolic disorder predominantly caused by the dysfunction of pancreatic β‑cells. This dysfunction is partly caused by the dysregulation of pyruvate dehydrogenase (PDH), which acts as an important mediator of pyruvate oxidation after glycolysis and fuels the tricarboxylic acid cycle. Previous studies have reported decreased PDH expression in rodent models and humans with type 2 diabetes mellitus (T2DM), suggesting that PDH may play an important role in the development of T2DM. However, the mechanism by which PDH affects insulin secretion and β‑cell development is poorly understood. Using immunofluorescence staining, the present study found that the expression of pyruvate dehydrogenase E1‑α subunit (PDHA1; encoded by the PDHA1 gene) in the islets of type 2 diabetic mice (db/db mice) was lower than in wild‑type mice, which indicated the possible association between PDHA1and diabetes. To further understand this mechanism, an inducible, islet‑specific PDHA1 knockout mouse (βKO) model was established. The phenotype was authenticated, and the blood glucose levels and islet function between the βKO and control mice were compared. Though no changes were found in food intake, development status, fasting blood glucose or weight between the groups, the level of insulin secretion at 30 min after glucose injection in the βKO group was significantly lower compared with the control group. Furthermore, the performed of the βKO mice on the intraperitoneal glucose tolerance test was visibly impaired when compared with the control mice. Pancreatic tissues were collected for hematoxylin and eosin staining, immunohistochemical and confocal laser‑scanning microscopy analysis. Examination of the islets from the βKO mouse model indicated that abolishing the expression of PDH caused a compensatory islet enlargement and impaired insulin secretion.

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